DESCRIPTION (from applicant's abstract): This is a competing continuation proposal of a grant funded to study the novel Jerky protein and its role in epilepsy. The mouse line defective in the jerky gene shows epileptic seizures and our work has shown that consistent with its mutant phenotype, jerky is transcribed at a relatively high level in neurons of the central nervous system and that Jerky binds mRNA. We also showed that antibodies recognizing Jerky are present in sera of patients suffering of a certain from of autoimmune neuronal degeneration (paraneoplastic disorders, PND). Other studies suggested that the human jerky gene is a candidate for childhood absence epilepsy (CAE). We now understand Jerky to be a prototypic member of an evolutionarily conserved family of RNA binding proteins (RNPs) containing a novel RNA binding motif. RNPs are trans-acting factors mediating posttranscriptional processing of mRNAs and pre-mRNAs, including splicing, polyadenylation, transport, targeting, stability and translation. We hypothesize that lack of Jerky in mutant mice leads to a deficiency in the processing of certain mRNAs compromising neuronal functions that results in seizures. We also show that lack of FMRP (Fragile X Mental Retardation Protein), another RNP whose inactivation causes fragile X syndrome and which is believed to be involved in mRNA processing, also results in seizures in mice. This finding is consistent with the high incidence of seizures in fragile X patients. Since FMRP-deficient animals represent a second example of a situation in which abnormalities in an RNP result in seizures, we suggest that RNP dysfunction may be more general disease mechanism in epilepsy. Due to the potential importance of RNPs in epilepsy, the focus of our current grant application is to study the cellular role of Jerky, Jerky-like proteins, and FMRP. We propose I) to analyze the RNA binding properties of the human JERKY protein and a similar human protein HHJRK, II) to identify the cellular binding targets of JERKY and FMRP (by a method recently developed in our laboratory) and to assign functions for these targets, and 3) to employ Jerky autoantibodies as tool to study Jerky-RNA complexes. These proposed experiments will establish the jerky family as a distinct group of RNPs with a novel RNA binding motif. Also, specifying targets for JERKY and FMRP will allow us to link these targets to cellular pathways and ascertain how these pathways contribute to the overall function of these proteins. Finally, these experiments will aid in our understanding of certain aspects of the pathogenesis of epilepsy and autoimmune diseases.